Psoriasis is a common, chronic inflammatory skin disease, affecting approximately 2% of the population. Psoriatic arthritis is also seen in about 10% of patients. Despite the fact that the disease has an autoimmune etiology and has been associated with HLA alleles, particularly those from the class I region, there is significant genetic heterogeneity and at least ten non HLA loci have been described. The penetrance of associated alleles within HLA is about 10% and it is believed that epistasis with some of these non HLA alleles is required for disease development. There may also be loci that are entirely HLA-dependent. Some genetic risk factors associated with psoriasis may also predispose to other inflammatory diseases. Identifying genes involved in complex traits has been facilitated by the significant progress made by the genome project. Besides making available genetic sequence from susceptibility regions, genome annotation has permitted the localization of candidate genes and the identification of potentially novel transcripts. The development and localization of a dense set of polymorphic markers in the form of single nucleotide polymorphisms (SNPs) is facilitating the localization of complex traits through association mapping. We have a cohort of 242 nuclear families and 25 multiply affected families with psoriasis that have been used to localize susceptibility genes with linkage and association. Our next goal is to identify these genes and the underlying predisposing variants. The regions under investigation have been identified in at least two independent studies with different psoriasis family sets and lie within chromosomes 1q21, 6p21, 10q22-q23 and 17q24.3. In order to reduce the amount of SNP genotyping that is performed, conserved haplotype blocks will be identified with a dense set of SNPs. A subset of SNPs found in each conserved block will be used to test for association with psoriasis in a set of 250 psoriasis cases/controls and 242 nuclear families. Variants will be identified by DNA sequencing and examined for their frequency in affected families and unrelated controls. Studies of epistasis between predisposing loci will also be performed. Gene identification may be facilitated by the comprehensive gene expression data we have recently acquired in comparing involved and uninvolved psoriatic skin with normal skin.